Avosentan reduces proteinuria, but has serious CV side effects
MedWire News: Study results show that the endothelin antagonist avosentan reduces proteinuria in individuals with Type 2 diabetes, but is associated with serious cardiovascular (CV) side effects.
These included significant fluid overload and congestive heart failure (HF) and led to the ASCEND (A Randomised, Double Blind, Placebo Controlled, Parallel Group Study to Assess the Effect of the Endothelin Receptor Antagonist Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death in Patients With Type 2 Diabetes Mellitus and Diabetic Nephropathy) trial being terminated at 4 months, say Giancarlo Viberti (Kings College London, UK) and team.
Research suggests that proteinuria, or albuminuria, is not only a biomarker of renal disease, but also contributes to progressive kidney damage ultimately leading to end-stage renal disease (ESRD).
Around 15–20% of patients with Type 2 diabetes and diabetic nephropathy develop ESRD after only 2.5–3.5 years, despite intensive treatment, indicating a need for new therapies.
In ASCEND, the effect of avosentan on time to doubling of serum creatinine, ESRD, or death was measured, as well as change in the albumin-to-creatinine ratio (ACR) in 1392 patients with Type 2 diabetes and diabetic nephropathy. Of these, 455 were randomly assigned to take avosentan 25 mg/day, 478 to take avosentan 50 mg/day, and 459 to take placebo.
Due to an excess of CV events in the avosentan groups, the trial was terminated early at 4 months. Overall, 204 and 219patients in the avosentan 25-mg/day and avosentan 50-mg/day groups, respectively, compared with 141 patients in the placebo group experienced fluid overload. In addition, a corresponding 27 and 29 versus 10 participants experienced congestive HF, and 68 and 71 versus 47 had a CV outcome (composite of coronary or peripheral vascular revascularization, amputations [except from trauma], nonfatal acute myocardial infarction, stroke, and congestive HF).
No difference in the primary outcome (time to doubling of serum creatinine, ESRD, or death) was observed between those treated with avosentan and placebo, but avosentan treatment did significantly reduce the ACR, with reductions of 44.3% and 49.3% versus 9.7% in the avosentan 25-mg/day and avosentan 50-mg/day compared with placebo groups, respectively.
Eberhard Ritz (Ruperto Carola University, Heidelberg, Germany) and René Wenzel (General Public Hospital Zell am See, Austria) commented in an accompanying editorial: “We suspect that lower dosages of endothelin antagonist receptor blockers may be associated with fewer adverse effects, and hopefully those dosages will be clinically effective.”
They add: “Before making any sweeping suggestions, however, it is absolutely necessary to have more information on the long-term safety of avosentan in the 5- to 10-mg/day dosage range.”
The results of this study are published in the Journal of the American Society of Nephrology.
MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010
By Helen Albert